Pediatric ASP Toolkit

Morbidity and mortality associated with antibiotic exposure: Multiple studies suggest that antibiotics carry potential risks for preterm infants treated for culture-negative infections (or treated for infections without culture-confirmation).

• Broad-spectrum antibiotic exposures, particularly cephalosporin use is associated with increased incidence of invasive fungal infections in preterm infants^2,3, with an attributable mortality of 13%.⁴ In a multicenter study that included 128,914 newborns of all gestational ages, empirical early treatment with a combination of ampicillin and cefotaxime, compared with ampicillin and gentamicin, was associated with higher mortality rates.⁵
• Perinatal and postnatal antibiotic exposures are also associated with subsequent colonization with resistant bacterial organisms and later infection.^6–10
• Association with development of NEC, BPD, and/or mortality:
  • One study of 5,693 ELBW infants cared for in 19 NRN centers found an association between prolonged initial antibiotic therapy (defined as antibiotics initiated at <3 days of age and continued for ≥5 days) and subsequent risk of NEC or death.¹¹
  • Prolonged initial empirical antibiotic use in VLBW infants cared for at three sites in Cincinnati was associated with the combination of late-onset sepsis, NEC or death.¹²
  • In a single center study of 1,140 VLBW infants, each additional day of antibiotic exposure in the first 14 days of age was associated with increased risk of death or bronchopulmonary dysplasia (BPD), as well as increasing severity of BPD.¹³ The relationship between early antibiotic exposure and development of NEC or BPD has been reported in other settings^6,14 and may have biologic plausibility in a link between antibiotic exposure and subsequent gastrointestinal and airway microbiome dysbiosis.^10,15
  • The Canadian multicenter study of VLBW infants without culture-confirmed infection or NEC found an association between infants in the highest AUR quartile and a composite outcome of mortality or “major morbidity” including persistent echogenicity or echolucency on neuroimaging, stage 3 or higher retinopathy of prematurity, or BPD.¹⁶ The association between the higher AURs and the composite outcome in this study was largely driven by the substantial increase in mortality among these infants.

Dysbiosis

• Early antibiotic exposure may initiate dysbiosis even among otherwise healthy term infants. There is evidence that early life antibiotics alter gut and airway microbiota.^15,21,22 The widespread use of peripartum (e.g., intrapartum and immediate neonatal) antibiotics and the demonstration that such exposures alter the initial composition of the newborn gut microbial composition raises the possibility that intrapartum infection prevention therapies may have later health consequences.²³ These concerns are supported by studies of early infancy and childhood antibiotic exposures. Canadian infants receiving antibiotics in the first year of age were more likely to be overweight in childhood.²⁴ In a Finnish population based-cohort, antibiotic exposure before 6 months of age or repeatedly during infancy was associated with increased body mass in early childhood, with a distinct relationship between broad-spectrum antibiotic exposure and subsequent increased body mass.²⁵

Long-term health consequences

• Studies also suggest a relationship between early antibiotic exposure and subsequent development of atopic diseases.^26–28,31 Asthma is the most common childhood chronic illness, with increasing prevalence over the last 4 decades.²⁹ Using a longitudinal birth cohort of infants in British Columbia born between 1997 and 2003, investigators found that use of antibiotics in the first year of age was associated with increased risk of developing asthma and that the risk increased as number of antibiotic prescriptions increased.²⁹ A systematic review of multiple studies addressing antibiotics administered in infancy and risk of childhood asthma found a pooled odds ratio of 1.52 (95% confidence interval [CI]: 1.30-1.77).²⁶ Multiple confounding factors may impact the relationships between early antibiotic exposure and subsequent obesity, asthma or allergic disease. Prospective studies of maternal, preterm and term infant antibiotic exposures and the impact on childhood outcomes are ongoing and will better inform the true risks and benefits of empiric antibiotic use in the perinatal and early life period.

1. Flannery DD, Puopolo KM. Neonatal Antibiotic Use: What Are We Doing and Where Shall We Go? Neoreviews. 2018;19(9):e516-e525.
2. Cotten CM, McDonald S, Stoll B, Goldberg RN, Poole K, Benjamin DK. The Association of Third-Generation Cephalosporin Use and Invasive Candidiasis in Extremely Low Birth-Weight Infants. Pediatrics. 2006;118(2):717-722.
3. Benjamin D et al. Neonatal Candidiasis: Epidemiology, Risk Factors, and Clinical Judgment. Pediatrics. 2010;126(4). doi:10.1542/peds.2009-3412
4. Fridkin SK. Changing Incidence of Candida Bloodstream Infections Among NICU Patients in the United States: 1995-2004. Pediatrics. 2006;117(5):1680-1687. doi:10.1542/peds.2005-1996
5. Clark RH. Empiric Use of Ampicillin and Cefotaxime, Compared With Ampicillin and Gentamicin, for Neonates at Risk for Sepsis Is Associated With an Increased Risk of Neonatal Death. Pediatrics. 2006;117(1):67-74. doi:10.1542/peds.2005-0179
6. Novitsky A, Tuttle D, Locke RGR, Saiman L, Mackley A, Paul DDA. Prolonged Early Antibiotic Use and Bronchopulmonary Dysplasia in Very Low Birth Weight Infants. Am J Perinatol. 2014;32(01):043-048.
7. Arboleya S, Sánchez B, Milani C, et al. Intestinal Microbiota Development in Preterm Neonates and Effect of Perinatal Antibiotics. J Pediatr. 2015;166(3):538-544. doi:10.1016/j.jpeds.2014.09.041
8. de Man P, Verhoeven B a, Verbrugh H a, Vos MC, van den Anker JN. An antibiotic policy to prevent emergence of resistant bacilli. Lancet. 2000;355:973-978. doi:10.1016/S0140-6736(00)90015-1
9. Patel SJ, Saiman L. Antibiotic Resistance in Neonatal Intensive Care Unit Pathogens: Mechanisms, Clinical Impact, and Prevention Including Antibiotic Stewardship. Clin Perinatol. 2010;37(3):547-563. doi:10.1016/j.clp.2010.06.004
10. Madan JC, Salari RC, Saxena D, et al. Gut microbial colonisation in premature neonates predicts neonatal sepsis. Arch Dis Child Fetal Neonatal Ed. 2012;97(6):F456-62. doi:10.1136/fetalneonatal-2011-301373
11. Greenberg RG, Chowdhury D, Hansen NI, et al. Prolonged duration of early antibiotic therapy in extremely premature infants. Pediatr Res. January 2019:1. doi:10.1038/s41390-019-0300-4
12. Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J Pediatr. 2011;159(5):720-725.
13. Cantey JB, Huffman LW, Subramanian A, et al. Antibiotic Exposure and Risk for Death or Bronchopulmonary Dysplasia in Very Low Birth Weight Infants. J Pediatr. 2017;181:289-293.e1.
14. Alexander VN, Northrup V, Bizzarro MJ. Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis. J Pediatr. 2011;159(3):392-397. doi:10.1016/j.jpeds.2011.02.035
15. Lal CV, Travers C, Aghai ZH, et al. The Airway Microbiome at Birth. Nat Publ Gr. 2016:1-13. doi:10.1038/srep31023
16. Ting JY, Synnes A, Roberts A, et al. Association Between Antibiotic Use and Neonatal Mortality and Morbidities in Very Low-Birth-Weight Infants Without Culture-Proven Sepsis or Necrotizing Enterocolitis. JAMA Pediatr. 2016;170(12):1181.
17. Wortham JM, Hansen NI, Schrag SJ, Hale E, Meurs K Van. Chorioamnionitis and Culture- Confirmed , Early-Onset Neonatal Infections. 2017;137(January 2016).
18. Mukhopadhyay S, Lieberman ES, Puopolo KM, Riley LE, Johnson LC. Effect of early-onset sepsis evaluations on in-hospital breastfeeding practices among asymptomatic term neonates. Hosp Pediatr. 2015;5(4):203-210.
19. Clock SA, Jia H, Patel S, et al. Infant Colonization With Methicillin-Resistant Staphylococcus aureus or Vancomycin-Resistant Enterococci Preceding Neonatal Intensive Care Unit Discharge. J Pediatric Infect Dis Soc. 2017;6(3):e144-e148. doi:10.1093/jpids/pix003
20. Peterson D, Hoffman SB, Driscoll CH. Management of asymptomatic neonates born in the setting of chorioamnionitis : a safety comparison of the well-baby and intensive care setting. 2017;37(11):1236-1241. doi:10.1038/jp.2017.120
21. Azad MB, Konya T, Persaud RR, et al. Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: A prospective cohort study. BJOG An Int J Obstet Gynaecol. 2016;123(6):983-993. doi:10.1111/1471-0528.13601
22. Cacho N, Neu J. Manipulation of the intestinal microbiome in newborn infants. Adv Nutr. 2014;5(1):114-118. doi:10.3945/an.113.004820
23. Bedford Russell AR, Murch SH. Could peripartum antibiotics have delayed health consequences for the infant? BJOG An Int J Obstet Gynaecol. 2006;113(7):758-765. doi:10.1111/j.1471-0528.2006.00952.x
24. Azad MB, Bridgman SL, Becker AB, Kozyrskyj AL. Infant antibiotic exposure and the development of childhood overweight and central adiposity. Int J Obes. 2014;38(10):1290-1298. doi:10.1038/ijo.2014.119
25. Saari A, Virta LJ, Sankilampi U, Dunkel L, Saxen H. Antibiotic Exposure in Infancy and Risk of Being Overweight in the First 24 Months of Life. Pediatrics. 2015;135(4):617-626.
26. Murk AW, Risnes KR. Prenatal or Early-Life Exposure to Antibiotics and Risk of Childhood Asthma : A Systematic Review. 2018;127(6). doi:10.1542/peds.2010-2092
27. Risnes KR, Belanger K, Murk W, Bracken MB. Original Contribution Antibiotic Exposure by 6 Months and Asthma and Allergy at 6 Years : Findings in a Cohort of 1 , 401 US Children. 2011;173(3):310-318. doi:10.1093/aje/kwq400
28. Russell SL, Gold MJ, Hartmann M, et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 2012;13(5):440-447. doi:10.1038/embor.2012.32
29. Marra F, Marra CA, Richardson K, Lynd LD. Antibiotic Use in Children Is Associated With Increased Risk of Asthma. 2018;123(3). doi:10.1542/peds.2008-1146
30. Chelimo C, Camargo CA, Morton SMB, Grant CC. Association of Repeated Antibiotic Exposure Up to Age 4 Years With Body Mass at Age 4.5 Years. JAMA Netw Open. 2020;3(1):e1917577.
31. Zven SE, Susi A, Mitre E, Nylund CM. Association Between Use of Multiple Classes of Antibiotic in Infancy and Allergic Disease in Childhood. JAMA Pediatr. 2019 Dec 20;174(2):199-200.